Use of tradipitant in motion sickness

ABSTRACT

Disclosed herein is a method of treating or preventing motion sickness or at least one symptom thereof, comprising treatment with the NK-1 receptor antagonist, tradipitant.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of co-pending U.S. applicationSer. No. 16/591,927, filed Oct. 3, 2019, which is a continuation ofco-pending International Application No. PCT/US19/53107, filed Sep. 26,2019, which in turn claims the benefit of U.S. Provisional ApplicationNo. 62/737,992, filed Sep. 28, 2018, and U.S. Provisional ApplicationNo. 62/874,927, filed Jul. 16, 2019. Each of the foregoing applicationsis incorporated by reference as though fully set forth herein.

BACKGROUND

The application relates generally to the use of NK-1 receptorantagonists. More particularly, the application relates the use of theNK-1 antagonist, tradipitant in motion sickness.

Motion sickness is a disorder defined by a constellation of symptomsthat can result from real or perceived sickness-inducing motion. Suchmotion may include, e.g., motion involving the head of a subject thatcan produce one or more symptoms characteristic of motion sickness. Thesickness-inducing motion that gives rise to motion sickness may commonlyinclude riding in any form of transportation such as, e.g., automobiles,buses, trains, other ground or rail transportation, boats under power,ferries, cruise ships, sailboats, personal water craft, canoes, kayaks,row boats, airplanes and helicopters, amusement rides, and certaingymnastic maneuvers such as somersaults. The symptoms of motion sicknesstypically can include, but are not limited to, nausea, vomiting,dizziness, headache, fullness, cold sweats, sweating, pallor,disorientation, and anorexia. Motion sickness has been reported toaffect up to 30% of the general population under ordinary travelconditions that include sea, air, and land travel. The prevalence ofmotion sickness in one epidemiological study during bus travel found 28%of passengers reporting feeling ill while 13% reported experiencingnausea.

Under the sensory conflict theory, motion sickness is described asarising due to a mismatch between the perceptions of motion, or lackthereof, by the visual, vestibular, and somatosensory systems. Adiscrepancy between actual body position and perceived body position isbelieved to trigger the maladaptive response of motion sickness. Motionsickness is one of the most prevalent episodic disorders in the world,and its prevalence has dramatically increased with world populationmobility. Despite the increasing prevalence of the disorder, thetreatments available today, which are primarily antihistamines andanticholinergics, were first discovered in the 1940's.

The mammalian tachykinins (neurokinins [NKs]) are a family of peptideneurotransmitters that share a common C-terminal sequence. This groupincludes substance P (SP), neurokinin-A (NKA), and neurokinin-B (NKB).SP, the most abundant NK, preferentially binds to the neurokinin type-1(NK-1) receptor and is involved in the regulation of many physiologicalprocesses. NK-1 receptors have been mapped in the central nervous systemand were found to have a broad distribution in the brain, including themid-brain, basal ganglia, hypothalamus, and limbic system. Neurokininreceptors are also widely distributed in the gut, the bronchial tree,and the vascular system.

The NK-1 receptor has been identified as a potential therapeutic targetfor the treatment of motion sickness. Maropitant, another neurokinin 1receptor antagonist, is approved for the prevention of vomiting due tomotion sickness in dogs and cats. A crossover study showed that thetherapy reduced the occurrence of vomiting in over 75% of dogs ascompared to placebo. This data supports the exploration of the effectsof NK-1 antagonists on motion sickness in humans, though maropitant hasa different molecular composition and pharmacokinetics from other NK-1antagonists. Another NK1-receptor antagonist, aprepitant, is approvedfor postoperative nausea and vomiting (PONV) in adults, and for use withother medications in children and adults to prevent nausea and vomitingcaused by certain anti-cancer (chemotherapy) medicines. Currently,tradipitant is being tested in clinical trials for the treatment ofnausea and vomiting in patients with gastroparesis. Currently, availabletherapies are not effective for all patients and some of the medicationsused have significant side effect profiles.

Tradipitant is a highly potent, selective, centrally penetrating, andorally active neurokinin-1 (NK-1) receptor antagonist, depicted below asthe compound of Formula (I)

Tradipitant is disclosed in U.S. Pat. No. 7,320,994, and contains sixmain structural components: the 3,5-bis-trifluoromethylphenyl moiety,two pyridine rings, the triazol ring, the chlorophenyl ring, and themethanone. Tradipitant is known by the chemical names:2-[1-[[3,5-bis(trifluoromethyl)phenyl]methyl]-5-(4-pyridinyl)-1H-1,2,3-triazol-4-yl]-3-pyridinyl](2-chlorophenyl)-methanone,and{2-[1-(3,5-bistrifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone,and has also been known as LY686017 and as VLY-686. Crystalline Forms IVand V of tradipitant are disclosed in U.S. Pat. No. 7,381,826, and aprocess for preparing crystalline{2-[1-(3,5-bistrifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone,Form IV is disclosed in U.S. Pat. Nos. 8,772,496; 9,708,291; and10,035,787.

In preclinical and clinical studies, tradipitant produces a long-lastingblockade of brain NK-1 receptors. Although the distinct pathways ofnausea and vomiting are largely undetermined, a definitive role of SPacting at NK-1 receptors in the nucleus tractus solitarus has beenconfirmed. Previous clinical studies have demonstrated the efficacy ofNK-1 antagonism in the prevention of chemotherapy induced andpost-operative nausea and vomiting (CINV and PONY).

BRIEF DESCRIPTION OF THE INVENTION

A first aspect of the invention provides a method of prevention ofmotion sickness or one or more symptoms thereof, in an individualanticipating experiencing sickness-inducing motion, comprisingadministering tradipitant to said individual in an amount effective toprevent manifestation of motion sickness or one or more symptomsthereof. In practicing the foregoing method, the amount of tradipitantthat is effective to prevent motion sickness or a symptom thereof maybe, e.g., 100-400 mg, 100-300 mg, or 100-200 mg. For example, theeffective amount can be about 170 mg. The effective amount may beadministered in a single dose, such as a single oral dose, and may ormay not be in a single dosage unit form. The dose may be administered inadvance of engaging in a sickness-inducing motion, typically about 30minutes before commencing such motion. Administration of such aneffective amount prior to commencing sickness-inducing motion canprevent or reduce the severity or frequency of one or more symptoms ofmotion sickness, including the prevention of nausea, vomiting,dizziness, headache, fullness, cold sweats, sweating, pallor, ordisorientation.

A second aspect of the invention provides a method of treating motionsickness or one or more symptoms thereof, in an individual experiencingthe manifestation of motion sickness, comprising administeringtradipitant to said individual in an amount effective to treat themotion sickness or the symptom thereof. Treatment of motion sickness maybe considered to include a reduction in severity of symptoms, theprevention of progression, or the complete resolution of one or moresymptoms of motion sickness after such symptom or symptoms have manifestin the individual. In practicing the foregoing method, the amount oftradipitant that is effective to treat motion sickness or a symptomthereof may be, e.g., 100-400 mg, 100-300 mg, or 100-200 mg. Forexample, the effective amount can be about 170 mg. The effective amountmay be administered in a single dose, such as a single oral dose, andmay or may not be in a single dosage unit form. The dose may beadministered after the onset of at least one symptom of motion sickness,preferably soon after the onset of the at least one symptom, and morepreferably, immediately after the onset of the at least one symptom.Administration of such an effective amount after motion sickness hasbegun to manifest can reduce the severity of the symptom(s), eliminatethe symptom(s), prevent the progression or intensification of thesymptom(s) of motion sickness, for example from dizziness to nausea,from nausea to vomiting, etc.

A third aspect of the invention provides tradipitant for use in any ofthe methods of treatment or prevention described in the precedingaspects.

A fourth aspect of the invention provides a pharmaceutical compositioncomprising tradipitant for use in any of the preceding methods oftreatment or prevention.

A fifth aspect of the invention provides tradipitant for use in themanufacture of a pharmaceutical composition comprising tradipitant foruse in any of the preceding methods of treatment or prevention.

These and other aspects, advantages and salient features of theinvention will become apparent from the following detailed description,which, when taken in conjunction with the annexed figure(s) discloseembodiments of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the effect of tradipitant on NK-1 agonist (GR73632, 3pmol, icv)-induced foot-tapping behavior after oral administration.

FIG. 2 illustrates the effect of tradipitant on NK-1 agonist (GR73632, 3pmol, icv)-induced foot-tapping behavior after oral administration:comparison with other NK-1 antagonists, aprepitant and CP-122721: doseresponse.

FIG. 3 illustrates the effect of tradipitant on NK-1 agonist (GR73632, 3pmol, icv)-induced foot-tapping behavior after oral administration:comparison with other NK-1 antagonists, aprepitant and CP-122721: timecourse.

FIG. 4 illustrates the effect of tradipitant on GR73632-inducedvocalization in guinea pigs across a concentration range of 0.05 to 10mg/kg.

FIG. 5 illustrates the duration of activity, i.e. suppression of NK-1agonist-induced vocalization in guinea pigs, following a 0.1 mg/kg doseof tradipitant.

FIG. 6 illustrates the dose-dependent effects of tradipitant, and theeffects of various NK-1 antagonists in the guinea pig vocalizationassay.

The drawings are intended to depict only typical aspects of thedisclosure, and therefore should not be considered as limiting the scopeof the disclosure.

DETAILED DESCRIPTION OF THE INVENTION

The method of using tradipitant as described herein requiresadministering an amount of tradipitant that is effective to prevent ortreat motion sickness or a symptom thereof. The amount administered to asubject being treated depends upon a number of factors, including thespecies being treated, the weight of the subject being treated, and thesubject's condition otherwise. The method specifically involves theprevention and amelioration of motion sickness in human beings,including adult human beings. In adult human beings the typical doseeffective to prevent motion sickness or a symptom thereof is 100-400 mg,100-300 mg, or 100-200 mg. One specific regime involves administrationof about 85-170 mg, or more particularly about 170 mg.

As used herein, the terms “patient,” “subject,” and “individual” referto a mammal who is administrated tradipitant. Guinea pigs, dogs, cats,gerbils, horses, cattle, sheep, and humans are within the scope of theterms “patient,” “subject,” and “individual.” The most preferred subjectis a human being. The term “effective amount,” i.e., dose, oftradipitant refers to an amount that is effective in treating orpreventing the disorders described herein, or symptoms thereof.

As indicated above, a method is provided herein for preventing motionsickness or a symptom thereof, in an individual anticipatingexperiencing sickness-inducing motion. Such method comprisesprophylactically administering tradipitant to said individual in anamount effective to prevent the manifestation of motion sickness or oneor more symptoms thereof. The effective amount of tradipitant to preventmotion sickness or a symptom thereof may be, e.g., 100-400 mg, 100-300mg, 100-200 mg, or 85-170 mg, and may particularly be about 170 mg. Theeffective amount may be administered in a single dose such as, e.g., asingle oral dose, and may or may not be in a single dosage unit form.The dose may be administered in advance of engaging in asickness-inducing motion, for example, in advance of boarding anairplane, train, boat, or other vehicle, or getting into an automobile,or before an anticipated airplane takeoff or commencement of motion onboard any other type of vehicle. Particularly, the dose may beadministered about thirty (30) minutes prior to commencement of thepotentially motion sickness-inducing motion or activity. Suchadministration of an effective amount of tradipitant can prevent themanifestation of one or more symptoms of motion sickness, including theprevention of nausea, vomiting, dizziness, headache, fullness, ordisorientation, or may limit the symptom(s) experienced by theindividual and the severity thereof.

A method is also provided herein for treating motion sickness or asymptom thereof after such motion sickness has already manifest or begunto manifest in the individual. Such method includes administeringtradipitant to said individual in an amount effective to treat themotion sickness or the symptom thereof. Treatment of motion sickness inthe present context includes all processes in which there may be aslowing, interrupting, arresting, controlling, or stopping of theprogression of motion sickness and/or symptoms thereof. For example,such treatment may include the prevention of progression, or the partialor complete resolution of one or more symptoms of motion sickness aftersuch symptom or symptoms have manifest in the individual. In practicingthe foregoing method, the amount of tradipitant that is effective totreat motion sickness or a symptom thereof may be, e.g., 100-400 mg,100-300 mg, 100-200 mg, 85- 170 mg, or particularly about 170 mg. Theeffective amount may be administered in a single dose, including asingle oral dose, which may or may not be in a single dosage unit form.The effective amount of tradipitant may be administered after the onsetof at least one symptom of motion sickness. Preferably, the effectiveamount is administered soon after the onset of the at least one symptom,for example up to thirty (30) minutes after the onset of the at leastone symptom, and more preferably, the effective amount is administeredimmediately or substantially immediately after the onset of the at leastone symptom. Administration of such an effective amount after motionsickness has begun to manifest can reduce the severity of thesymptom(s), eliminate the symptom(s), or prevent the progression orintensification of the symptom(s) of motion sickness, for example fromdizziness to nausea, from nausea to vomiting, etc.

The skilled artisan will appreciate that additional preferredembodiments may be selected by combining the preferred embodimentsabove, or by reference to the examples given herein.

EXAMPLES Example 1: Pre-Clinical Studies

Tradipitant is a selective neurokinin-1 (NK-1) receptor antagonist. Invitro, tradipitant potently inhibits NK-1 receptor binding andantagonizes the effects of an NK-1 agonist in a functional assay. Nosignificant activity is observed in a panel of 74 additional receptors,enzymes, and ion channels including the NK-2 and NK-3 receptors. By 3different measures, tradipitant is also a potent centrally active NK-1antagonist in vivo.

Example 1.1: Mechanism Studies

Tradipitant inhibits [¹²⁵I] substance P (SP) binding to the NK-1receptor expressed by IM-9 cells with a K_(i) of 0.062 nM and inhibitsthe SP-induced mobilization of intracellular calcium in U373 cells witha K_(b) of 0.095 nM (Table 1).

TABLE 1 Affinity of tradipitant for NK-1 Receptors In Vitro IM-9 HumanCell Calcium Mobilization in Antagonist Membrane Binding K_(i) (nM) U373Cells K_(b) (nM) Tradipitant 0.062 ± 0.012 0.095 ± 0.025 Aprepitant 0.14± 0.03 0.14 ± 0.01 CP-122721 0.027 ± 0.01  0.034 ± 0.009These potencies are similar to those observed with the NK-1 antagonistsaprepitant (MK-869) and CP-122721. In addition, results from tradipitantevaluation in a panel of 74 other receptors, enzymes, and ion channelsindicate that, at a test concentration of 1 μM, tradipitant does notexhibit any inhibition of binding greater than 50%. At the NK-2 and NK-3receptors, the compound produces no significant inhibition. Therefore,tradipitant is a highly selective NK-1 antagonist in vitro.

As shown in Table 2, several of the major metabolites of tradipitanthave an affinity for the NK-1 receptor based on a binding assay. Thesemetabolites have high affinity for the NK-1 receptor.

TABLE 2 Affinity of tradipitant metabolites for NK-1 Receptors in vitroIM-9 Human Cell Membrane Binding K_(i) Metabolite Designation (nM)LSN2081070 M2 (Racemic) 0.09 (n = 1) LSN2107355 M2 (S-enantiomer) 0.08(n = 1) LSN2107357 M2 (R-enantiomer) 0.94 (n = 1) LSN2195411 M3 0.03 (n= 1) LSN2195413 M4 (Racemic) 0.08 (n = 1)

Example 1.2: Efficacy Models for in vivo Evaluation of Brain NK-1Receptor Occupancy and Efficacy of Tradipitant

Example 1.2.1: Effects of Tradipitant on Centrally Administered NK-1Agonist-Induced Foot-Tapping Behavior in Gerbils

Introduction

Differences in species selectivity of NK-1 receptors pose challenges tocharacterization of NK-1 receptor antagonists in vivo. Gerbil NK-1receptors have previously been shown to be similar to those in humans.Gerbils exhibit a characteristic stereotypic foot-tapping behavior inresponse to distress, fear, or aversive stimuli. Intracerebroventricular(icy) administration of substance P or a selective NK-1 receptor agonistsuch as GR73632 produces rapid rhythmic tapping of the hind feet lastingapproximately 5 minutes, which can be inhibited by systemicadministration of a brain penetrating antagonist of the NK-1 receptor.This response is selective for NK-1 agonists, since selective NK-2 andNK-3 agonists do not elicit a similar response. This behavioral responseis further characterized and modified to enable identification andoptimization, in vivo, of potent NK-1 receptor antagonists includingtradipitant.

Methods

Male Mongolian gerbils (Harlan Sprague Dawley, Indianapolis, Ind.)weighing 26 to 40 grams are administered the selective neurokinin-1receptor agonist GR73632 (3 pmol) via direct, vertical, free-handintracerebroventricular (icy) injection to a depth of 4.5 mm belowbregma with a cuffed 27-gauge needle attached to a 50 μl Hamiltonsyringe. Immediately after injection, animals are placed individuallyinto isolated chambers with pressure-sensitive velocimeter platformfloors (San Diego Instruments acoustic startle apparatus) that detectand quantify vibration. The San Diego Instruments “SR” DOS-basedcomputer program is used on a PC to record the number of foot-taps overthe following 6 to 10 minutes, beginning 30 seconds after the floor islightly tapped. Raw data are converted with a Microsoft® Excel®(Microsoft® and Excel® are registered trademarks of Microsoft Corp.,Redmond, Wash.) macro that determines the number of events overthreshold (125) in each 250-millisecond time bin over the 5.5 minutesfollowing onset of observation. The total number and average intensityof events over the duration is determined. Total number of taps isanalyzed with one-way ANOVA and post-hoc Dunnett's test using JMPstatistical software.

A dose-response curve (with doses of 0.3, 1, 3 and 10 pmols, icv) isinitially generated with the NK-1 agonist GR73632. Maximal foot-tappingbehavior is achieved with 3 and 10 pmol doses; the 3 pmol dose issubsequently chosen as the dose of choice for antagonism experiments.

NK-1 antagonists are tested for their ability to attenuateGR73632-induced foot tapping. NK-1 antagonists are administered (po) viaoral feeding tube at doses and time points specified in each experiment.All animals receive only one dose of NK-1 antagonists in all tests.

ED₅₀ Determinations/Dose-Response Tests

NK-1 antagonists are administered at multiple doses (at least 3; onedose per animal) and response to GR73632 is measured.

Duration of Action Tests

NK-1 receptor antagonists are administered at multiple pre-treatmenttimes (one administration per animal) including at 0.5, 1, 2, 4, 7, 16,and 24 hours prior to GR73632 injection. GR73632 (Peninsula Labs,Calif.) is dissolved in saline. Tradipitant is dissolved in 1% CMC/0.5%SLS/0.085% PVP vehicle. CP-122721 and aprepitant are synthesized atLilly Laboratories and dissolved in 10% ethanol/emulphor and 1% CMC/0.5%SLS/0.085% PVP respectively.

Results

As shown in FIG. 1, orally administered tradipitant potently inhibitsNK-1 agonist-induced foot-tapping behavior in gerbils 2 hours afteradministration of drug in a dose-dependent manner, with an ED₅₀ of0.03±0.004 mg/kg (*p<0.05 compared to vehicle for 0.1 mg/kg and 0.3mg/kg doses). Data shown in FIG. 1 are expressed in number offoot-tapping events occurring in five (5) minutes.

FIG. 2 depicts a comparison of the efficacy of tradipitant to that ofother NK-1 antagonists, with data expressed as percent control ofvehicle (vehicle response to 3 pmol GR73632). Tradipitant is found to bemore potent than aprepitant (Merck, ED₅₀=0.42 mg/kg±0.05 mg/kg) andCP-122721 (Pfizer, ED₅₀=2.2 mg/kg±0.5 mg/kg).

FIG. 3 depicts the effects of tradipitant over a time course on NK-1agonist (GR 73632, 3 pmol, icv)-induced foot-tapping behavior after oraladministration, compared with that of NK-1 antagonists aprepitant andCP-122721. Tradipitant (0.1 mg/kg, po) is found to significantly inhibitfoot-tapping behavior up to 7 hours after administration but the effectis significantly diminished by 16 hours after administration at thisdose. However, at a higher dose of 1 mg/kg, tradipitant shows greaterthan 50% inhibition of foot-tapping behavior 16 hours afteradministration. The duration of effect of tradipitant is longer thanthat of CP-122721 (up to 2 hours after administration, 3 mg/kg) whileaprepitant (1 mg/kg) shows inhibition of foot-tapping behavior up to 24hours after administration. Data are expressed as percent control ofvehicle (vehicle response to 3 pmol GR73632).

Discussion

The effect of tradipitant on NK-1 agonist-induced foot-tapping behaviorin gerbils suggests that tradipitant is a very potent, centrally actingNK-1 receptor antagonist in vivo in the gerbil with a relatively longduration of action.

Example 1.2.2: Emetic Challenge Study in Beagle Dogs with Tradipitant

Introduction

Five male dogs are administered a single oral dose of 3 mg/kg aprepitant(a positive control), or tradipitant at 0.3, 1.0, and 3.0 mg/kg in aLatin-square design. An intravenous injection of 0.1 mg/kg apomorphine,a known emetic, is given alone, or 2 hours after administration oftradipitant or aprepitant. Each animal is administered a different doseon a particular dosing day, so that each dose of tradipitant,aprepitant, and apomorphine alone is represented. Over the five (5)weeks of the study, each animal receives each of the treatments, butonly one per week. The purpose of this study is to determine iftradipitant suppresses apomorphine-induced emesis.

The low dose of tradipitant is 10 times the ED₅₀ in the gerbilfoot-tapping model of NK-1 receptor antagonism (Example 1.2.1). The highdose is 100 times this efficacious dose, and is also the dose ofaprepitant that has previously been determined to be efficacious againstapomorphine-induced emesis in the dog. The mid dose of tradipitant isthe approximate half-log interval between the low and high doses.

The oral route of administration is selected for tradipitant becausethis is the route proposed or currently used clinically. The intravenousroute is typically used for experimental apomorphine administration. Thebeagle dog is considered an effective species for demonstration ofantagonism of apomorphine-induced emesis.

Methods

A single oral dose of 0, 0.3, 1.0, or 3.0 mg/kg tradipitant, or 3.0mg/kg aprepitant is administered to each male dog once a week in gelatincapsules. All animals are dosed over a period of five (5) weeks, witheach dog receiving one of five different treatments on each day ofdosing. A dose of 0.1 mg/kg apomorphine is administered by intravenousinjection approximately two (2) hours after each administration oftradipitant or aprepitant. In cases where apomorphine is administeredalone, without prior treatment with tradipitant or aprepitant,apomorphine is given at approximately the same time as when given incombination with tradipitant or aprepitant.

All dogs are fasted overnight prior to each treatment day and then fedapproximately one (1) hour after oral dosing (approximately one (1) hourprior to administration of apomorphine). Individual doses are adjustedweekly for changes in body weight.

The dose regimen consists of a 5×5 Latin square design, in which eachsubject receives 1 dose or dose combination per week (6 day washout) asshown in Table 3 below.

TABLE 3 Latin Square Design Study Study Study Study Study week 1 week 2week 3 week 4 week 5 Dog 1 APO + 0.3 APO + APO + 3 APO APO + 1 mg/kgaprepitant mg/kg mg/kg tradipitant tradipitant tradipitant Dog 2 APO +APO + 1 APO APO + 0.3 APO + 3 aprepitant mg/kg mg/kg mg/kg tradipitanttradipitant tradipitant Dog 3 APO + 3 APO APO + APO + 1 APO + 0.3 mg/kgaprepitant mg/kg mg/kg tradipitant tradipitant tradipitant Dog 4 APOAPO + 0.3 APO + 1 APO + 3 APO + mg/kg mg/kg mg/kg aprepitant tradipitanttradipitant tradipitant Dog 5 APO + 1 APO + 3 APO + 0.3 APO + APO mg/kgmg/kg mg/kg aprepitant tradipitant tradipitant tradipitantThe number of emetic episodes is recorded for approximately one hourfollowing the injection of apomorphine, and plasma concentrations atanticipated Tmax of tradipitant (2 hours post-dosing) are evaluated.

Results

Table 4 provides individual and mean and standard deviation values forthe 2 hour plasma concentrations of tradipitant. All animalsadministered tradipitant have measurable levels at 2 hours post-dose. Ingeneral, plasma concentrations at 2 hours post-dose increase withincreasing dose in a sub-proportional manner. As observed in otherstudies in dogs, the exposure to tradipitant is variable betweenanimals. Individual animal data reveal no relationship between plasmaconcentrations and week of administration.

TABLE 4 Plasma concentrations of tradipitant (ng/ml) Administered Dose0.3 mg/kg 1.0 mg/kg 3.0 mg/kg Concentration of Concentration ofConcentration of tradipitant (ng/ml) tradipitant (ng/ml) tradipitant(ng/ml) Dog 1 51.20 175.58 122.73 Dog 2 41.33 86.49 256.58 Dog 3 90.93240.84 316.20 Dog 4 83.38 100.97 682.91 Dog 5 22.59 61.56 119.79 Mean(SD) 57.89 (28.75) 133.09 (73.71) 299.64 (230.58)

As shown in Table 5, emesis occurs after each treatment, with thelargest incidence of emesis occurring in the apomorphine alone group.One dog (Dog 3) has a single episode of emesis at each dose oftradipitant and aprepitant; this dog also has the greatest number ofemetic episodes with apomorphine alone (12). No emesis occurs in theremaining four (4) dogs at any dose of tradipitant or aprepitant. Thesedogs have an average of four (4) emetic episodes with apomorphine alone.The antiemetic effect of aprepitant supports the validity of this model.

TABLE 5 Emetic episodes by treatment group Total No. Emetic Testarticle* Dose level (mg/kg) Episodes APO (control) 0 28   aprepitant 3.01** tradipitant 0.3 1** tradipitant 1.0 1** tradipitant 3.0 1***Apomorphine is administered as a challenge dose to all groups. **Allepisodes occur in same dog (Dog 3).

Results of this study indicate that tradipitant is effective againstapomorphine-induced emesis at each dose tested (0.3, 1.0, and 3.0mg/kg).

Example 1.2.3: Tradipitant Inhibits Substance P-Induced Vocalization inGuinea Pigs

Introduction

When introduced into the brain, the NK-1 receptor agonist substance P(SP) elicits distress vocalizations in the guinea pig that can beinhibited by NK-1 antagonists.

This behavioral assay is used to demonstrate potency and CNS penetrationof NK-1 antagonists in the guinea pig, a species that has receptoraffinity for NK-1 antagonists that is similar to humans.

Methods

Male Dunkin/Hartley guinea pigs (200 to 250 grams) are orallyadministered either vehicle or an NK-1 antagonist. Approximately 45minutes later (for dose response studies), the animals are anesthetizedand 0.1 nmol of GR73632 (SP analog) in a vehicle volume of 5 μl isinjected into the cerebral ventricle at the intersection of bregma andthe midline of the skull. Animals are placed in a dark testing chamberlocated inside of a sound attenuation cubicle and vocalizations arerecorded for 30 minutes following recovery from anesthesia. The timespent vocalizing is quantified for each animal. In the duration ofaction study, 0.1 mg/kg of tradipitant or vehicle solution isadministered orally and then 2, 4, or 7 hours later, 0.1 nmol of GR73632is administered into the cerebral ventricle as described above.Vocalizations are recorded and quantified as indicated above. Vehiclesolutions are either CMC (FIG. 4 data) or an ethanol/emulphor solution(FIGS. 5 and 6). Data is analyzed using one-tailed t-tests.

Results

As shown in FIG. 4, oral administration of tradipitant producessignificant inhibition of agonist-induced vocalization at doses of 10mg/kg (p<.001), 1.0 mg/kg (p<0.001), 0.1 mg/kg (p<.001), and 0.05 mg/kg(p<.001). Data shown parenthetically in FIG. 4 indicate percent ofcontrol response. Activity of tradipitant does not wane at the lowerdoses, indicating that even lower doses would be required to produce adose response function.

As shown in FIG. 5, the effect of 0.1 mg/kg tradipitant is significantlyactive in suppressing agonist-induced vocalization at 7 hours followingoral administration of the antagonist compound.

A second dose-response study compares potencies of tradipitant,aprepitant, and CP-122721. As shown in FIG. 6, all NK-1 antagoniststested produce significant inhibition of vocalization at 1 mg/kg. Onlytradipitant retains significant inhibitory activity at and below 0.1mg/kg. The minimum effective dose of tradipitant is found to be 0.025mg/kg which produces highly significant (p<.001) inhibition ofvocalization compared to controls. (Vehicle was ethanol/emulphor;vehicle groups were n=5−14 per compound.)

Discussion

Tradipitant significantly inhibits NK-1 agonist-induced vocalization inguinea pigs, indicating that this compound is an orally available andbrain-penetrant NK-1 antagonist. The minimum effective dose (MED) thatproduces this effect is 0.025 mg/kg. Tradipitant, administered orally,is shown to have a duration of activity that exceeds 7 hours. In thisexperimental paradigm, tradipitant is substantially more potent thanaprepitant and CP-122721.

Example 1.2.4: Occupancy of NK-1 Receptors

A tracer NK-1 antagonist compound (GR205171) is used to evaluate theability of other NK-1 antagonists to occupy the brain NK-1 receptors. Inthese studies, the test compounds are administered orally and the tracercompound is administered intravenously afterward. The occupancy of theNK-1 receptors is evaluated by quantitating the amount of the tracercompound bound to the brain NK-1 receptors after increasing doses of thetest compounds. Using this paradigm, tradipitant has an estimated ED₅₀of 0.04 mg/kg p.o. and is substantially more potent than the otherantagonists evaluated.

Example 2: Clinical Study of Gastrointestinal Motility

A single-center, randomized, double-blind, placebo-controlled study isconducted to investigate the effect of tradipitant on small boweltransit time. A total of 15 healthy subjects, including 12 men and 3women between the ages of 19 and 63 years, are enrolled in the study andreceive at least 1 dose of study medication. A total of 13 subjectscomplete the study. Subjects are randomized to receive 20 mg oftradipitant, 200 mg of tradipitant, or placebo as a single oral dosewithin each of 3 periods, co-administered with a capsule radiolabeledwith a maximum of 1 MBq ¹¹¹In. Four hours post-dose, all subjects alsoreceive a second capsule radiolabeled with a maximum of 4 MBq ^(99m)Tc.Each subject receives all 3 doses during the study. For all dosingregimens, in vivo gamma scintigraphic studies are performed atpredetermined intervals, and the following scintigraphic parameters areanalyzed: onset and completion of gastric emptying, onset and completionof colon arrival, initiation and completion of small bowel transit, andinitial and complete disintegration of the capsule (anatomical locationand time).

A statistically significant effect of tradipitant on small bowel transittime is observed in the study. No effect on gastric emptying is observedin this study. However, the study is underpowered with respect to thisparameter.

Example 3: Motion Sickness Prevention

A randomized, double blind, placebo-controlled clinical study of motionsickness is conducted, in which 126 human subjects (“studyparticipants”), each having a prior history of motion sickness, aresubjected to sea travel in the Pacific Ocean under varied weatherconditions.

Methods

Study participants are distributed over seven boat trips off the coastof Los Angeles, Calif., USA. For each trip, sea conditions andparticipant self-evaluation of symptoms of motion sickness are recorded.Among the seven trips, three are under “rough” sea conditions, conduciveto producing motion sickness with wave heights above one meter. Theremaining four trips are made under “calm” conditions, with wave heightsless than one meter, and are less likely to produce motion sickness.Under “rough” sea conditions, 72.2% of the placebo treated patientsexperience vomiting compared to only 26.7% under “calm” conditions.

Subjects are randomized to receive either tradipitant 170 mg or placeboby mouth in a blinded fashion, prior to travel initiation. Participantsreport their symptoms at predetermined time intervals during the travelperiod. Primary end points of the study include: percentage ofparticipants vomiting, and Motion Sickness Severity Scale (MSSS) Worstscore. The MSSS is a 7 point scale ranging from 0 (“no symptoms”) to 6(“vomiting”). An exploratory analysis is also performed to evaluate theeffects of tradipitant under “calm” and “rough” seas.

Results

Results are reported in Table 6 below. In the overall intent to treat(ITT) population (n=126), a significantly higher percentage ofparticipants experience vomiting in the placebo arm of the study (39.7%)as compared to the tradipitant arm (17.5%), p value=0.0039. The MSSSWorst score endpoint also favors tradipitant (3.4) vs. placebo (3.75),although the difference does not reach statistical significance, pvalue=0.293. Under “calm” sea conditions, only a small percentage ofparticipants in either arm experience vomiting, 26.7% in the placebo armand 18.2% in the tradipitant treatment arm (not significant). A similarMSSS Worst score is seen between the two groups under “calm” conditions,3.32 (placebo arm) and 3.40 (tradipitant treatment arm) (notstatistically significant). Under “rough” sea conditions, 72.2% of theplacebo treated patients vomit as compared to 15.8% of those treatedwith tradipitant, p value=0.0009. A significant effect is also seenunder “rough” conditions in the MSSS Worst score, 4.57 (placebo) and3.19 (tradipitant), p value=0.0235.

TABLE 6 Results for the Overall population and for the Calm and RoughSea sub-populations. Tradipitant Placebo Difference P-value ITT* n = 63n = 63 % Vomiting 17.5% 39.7% 22.2% 0.0039 Worst MSSS 3.40 3.75 0.350.2936 Calm Sea n = 44 n = 45 % Vomiting 18.2% 26.7% 8.5% 0.3123 WorstMSSS 3.4 3.32 −0.09 0.8271 Rough Sea n = 19 n = 18 % Vomiting 15.8%72.2% 56.4% 0.0009 Worst MSSS 3.19 4.57 1.38 0.0235

Conclusions

The foregoing data show that treatment with 170 mg tradipitant by mouthprior to travel initiation provides a significant reduction in theincidence of vomiting and in MSSS Worst score during travel under roughsea conditions and in overall conditions, as well as modest (notstatistically significant) reductions during travel under calmconditions. These findings show that tradipitant at a dose of 170 mgprovides an effective treatment for motion sickness.

EMBODIMENTS

In addition to other illustrative embodiments, this invention can beseen to comprise one or more of the following illustrative embodiments:

1. A method of treating a subject about to engage in an activityinvolving sickness-inducing motion comprising: administering tradipitantto said subject, prior to the commencement of said activity, in anamount effective to prevent motion sickness or at least one symptom ofmotion sickness in said subject.

2. The method of embodiment 1, wherein said activity is vehicle travel.

3. The method of either of embodiments 1 or 2, wherein saidadministration occurs about 30 minutes prior to entering a vehicle.

4. The method of either of embodiments 1 or 2, wherein theadministration occurs about 30 minutes prior to commencement of vehicletravel.

5. A method of treating a subject with motion sickness or at least onesymptom of motion sickness, comprising: administering tradipitant tosaid subject in an amount effective to treat said sickness or a symptomthereof.

6. The method of any of embodiments 1-5, wherein the effective amount is100-400 mg.

7. The method of any of embodiments 1-5, wherein the effective amount is100-300 mg.

8. The method of any of embodiments 1-5, wherein the effective amount is100-200 mg.

9. The method of any of embodiments 1-5, wherein the effective amount isabout 170 mg.

10. The method of any preceding embodiment, wherein the administrationfurther comprises oral administration of the effective amount oftradipitant.

11. The method of embodiment 10, wherein the tradipitant administered tothe subject is in a solid immediate release form such as a capsule ortablet comprising tradipitant and one or more pharmaceuticallyacceptable excipients.

12. The method of any one of embodiments 2-4, wherein the vehicle travelis via automobile, airplane, helicopter, boat, train, bus, or othervehicle.

13. The method of any preceding embodiment, wherein the at least onesymptom is nausea, vomiting, dizziness, headache, fullness, ordisorientation.

14. Tradipitant for use in any of the preceding methods of treatment.

15. A pharmaceutical composition comprising tradipitant for use in anyof the preceding methods.

16. Tradipitant for use in the manufacture of a pharmaceuticalcomposition comprising tradipitant for use in any of the precedingmethods.

As used herein, the terms “first,” “second,” and the like, do not denoteany order, quantity, or importance, but rather are used to distinguishone element from another, and the terms “a” and “an” herein do notdenote a limitation of quantity, but rather denote the presence of atleast one of the referenced item. The modifier “about” used inconnection with a quantity is inclusive of the stated value and has themeaning dictated by the context (e.g., includes the degree of errorassociated with measurement of the particular quantity). The suffix“(s)” as used herein is intended to include both the singular and theplural of the term that it modifies, thereby including one or more ofthat term (e.g., the metal(s) includes one or more metals). Rangesdisclosed herein are inclusive and independently combinable (e.g.,ranges of “up to about 25 mg, or, more specifically, about 5 mg to about20 mg,” is inclusive of the endpoints and all intermediate values of theranges of “about 5 mg to about 25 mg,” etc.).

While various embodiments are described herein, it will be appreciatedfrom the specification that various combinations of elements, variationsor improvements therein may be made by those skilled in the art, and arewithin the scope of the invention. In addition, many modifications maybe made to adapt a particular situation or material to the teachings ofthe invention without departing from essential scope thereof. Therefore,it is intended that the invention not be limited to the particularembodiment disclosed as the best mode contemplated for carrying out thisinvention, but that the invention will include all embodiments fallingwithin the scope of the appended claims.

We claim:
 1. A method of treating a subject about to engage in anactivity involving sickness-inducing motion comprising: administeringtradipitant to said subject, prior to the commencement of said activity,in an amount effective to prevent motion sickness or at least onesymptom of motion sickness in said subject.
 2. The method of claim 1,wherein said activity is vehicle travel.
 3. The method of claim 2,wherein said administration occurs about 30 minutes prior to entering avehicle.
 4. The method of claim 2, wherein said administration occursabout 30 minutes prior to commencement of vehicle travel.
 5. The methodof claim 1, wherein said effective amount is 100-400 mg.
 6. The methodof claim 5, wherein said effective amount is 100-300 mg.
 7. The methodof claim 6, wherein said effective amount is 100-200 mg.
 8. The methodof claim 7, wherein said effective amount is about 170 mg.
 9. The methodof claim 1, further comprising orally administering said effectiveamount of tradipitant.
 10. The method of claim 9, wherein saidtradipitant is orally administered in a solid immediate release formsuch as a capsule or tablet comprising tradipitant and one or morepharmaceutically acceptable excipients.
 11. The method of claim 2,wherein said vehicle travel is via automobile, airplane, helicopter,boat, train, or bus.
 12. The method of claim 1, wherein said at leastone symptom is nausea, vomiting, dizziness, headache, fullness, ordisorientation.
 13. A method of treating a subject with motion sicknessor at least one symptom of motion sickness, comprising: administeringtradipitant to said subject in an amount effective to treat saidsickness or a symptom thereof.
 14. The method of claim 13, wherein saideffective amount is 100-400 mg.
 15. The method of claim 14, wherein saideffective amount is 100-300 mg.
 16. The method of claim 15, wherein saideffective amount is 100-200 mg.
 17. The method of claim 16, wherein saideffective amount is about 170 mg.
 18. The method of claim 13, whereinsaid administration further comprises oral administration oftradipitant.
 19. The method of claim 18, wherein said tradipitant isorally administered in a solid immediate release form such as a capsuleor tablet comprising tradipitant and one or more pharmaceuticallyacceptable excipients.
 20. The method of claim 13, wherein said at leastone symptom is nausea, vomiting, dizziness, headache, fullness, ordisorientation.